Association of Transforming Growth Factor β Polymorphism C-509T With Radiation-Induced Fibrosis Among Patients With Early-Stage Breast Cancer

A Secondary Analysis of a Randomized Clinical Trial

Aaron Grossberg, Xiudong Lei, Ting Xu, Simona F. Shaitelman, Karen E. Hoffman, Elizabeth S. Bloom, Michael C. Stauder, Welela Tereffe, Pamela J. Schlembach, Wendy A. Woodward, Thomas A. Buchholz, Benjamin D. Smith

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Importance: Whether genetic factors can identify patients at risk for radiation-induced fibrosis remains unconfirmed. Objective: To assess the association between the C-509T variant allele in the promoter region of TGFB1 and breast fibrosis 3 years after radiotherapy. Design, Setting, and Participants: This is an a priori-specified, prospective, cohort study nested in an open-label, randomized clinical trial, which was conducted in community-based and academic cancer centers to compare hypofractionated whole-breast irradiation (WBI) (42.56 Gy in 16 fractions) with conventionally fractionated WBI (50 Gy in 25 fractions) after breast-conserving surgery. In total, 287 women 40 years or older with pathologically confirmed stage 0 to IIA breast cancer treated with breast-conserving surgery were enrolled from February 2011 to February 2014. Patients were observed for a minimum of 3 years. Outcomes were compared using the 1-sided Fisher exact test and multivariable logistic regression. Exposures: A C-to-T single-nucleotide polymorphism at position -509 relative to the first major transcription start site (C-509T) of the TGFB1 gene. Main Outcomes and Measures: The primary outcome was grade 2 or higher breast fibrosis as assessed using the Late Effects Normal Tissue/Subjective, Objective, Medical Management, Analytic scale (range, 0 to 3) three years after radiotherapy. Results: Among 287 women enrolled in the trial, TGFB1 genotype and 3-year radiotherapy-induced toxicity data were available for 174 patients, of whom 89 patients (51%) with a mean (SD) age of 60 (8) years had at least 1 copy of C-509T. Grade 2 or higher breast fibrosis was present in 12 of 87 patients with C-509T (13.8%) compared with 3 of 80 patients without the allele variant (3.8%) (absolute difference, 10.0%; 95% CI, 1.7%-18.4%; P =.02). The results of multivariable analyses indicated that only C-509T (odds ratio, 4.47; 95% CI, 1.25-15.99; P =.02) and postoperative cosmetic outcome (odds ratio, 7.09; 95% CI, 2.41-20.90; P <.001) were significantly associated with breast fibrosis risk. Conclusions and Relevance: To date, this study seems to be the first prospective validation of a genomic marker for radiation fibrosis. The C-509T allele in TGFB1 is a key determinant of breast fibrosis risk. Assessing TGFB1 genotype may facilitate a more personalized approach to locoregional treatment decisions in breast cancer.

Original languageEnglish (US)
Pages (from-to)1751-1757
Number of pages7
JournalJAMA Oncology
Volume4
Issue number12
DOIs
StatePublished - Dec 1 2018

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Radiation Pneumonitis
Transforming Growth Factors
Breast
Randomized Controlled Trials
Breast Neoplasms
Fibrosis
Radiotherapy
Segmental Mastectomy
Alleles
Odds Ratio
Genotype
Transcription Initiation Site
Genetic Promoter Regions
Cosmetics
Single Nucleotide Polymorphism
Cohort Studies
Logistic Models
Outcome Assessment (Health Care)
Prospective Studies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Association of Transforming Growth Factor β Polymorphism C-509T With Radiation-Induced Fibrosis Among Patients With Early-Stage Breast Cancer : A Secondary Analysis of a Randomized Clinical Trial. / Grossberg, Aaron; Lei, Xiudong; Xu, Ting; Shaitelman, Simona F.; Hoffman, Karen E.; Bloom, Elizabeth S.; Stauder, Michael C.; Tereffe, Welela; Schlembach, Pamela J.; Woodward, Wendy A.; Buchholz, Thomas A.; Smith, Benjamin D.

In: JAMA Oncology, Vol. 4, No. 12, 01.12.2018, p. 1751-1757.

Research output: Contribution to journalArticle

Grossberg, A, Lei, X, Xu, T, Shaitelman, SF, Hoffman, KE, Bloom, ES, Stauder, MC, Tereffe, W, Schlembach, PJ, Woodward, WA, Buchholz, TA & Smith, BD 2018, 'Association of Transforming Growth Factor β Polymorphism C-509T With Radiation-Induced Fibrosis Among Patients With Early-Stage Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial', JAMA Oncology, vol. 4, no. 12, pp. 1751-1757. https://doi.org/10.1001/jamaoncol.2018.2583
Grossberg, Aaron ; Lei, Xiudong ; Xu, Ting ; Shaitelman, Simona F. ; Hoffman, Karen E. ; Bloom, Elizabeth S. ; Stauder, Michael C. ; Tereffe, Welela ; Schlembach, Pamela J. ; Woodward, Wendy A. ; Buchholz, Thomas A. ; Smith, Benjamin D. / Association of Transforming Growth Factor β Polymorphism C-509T With Radiation-Induced Fibrosis Among Patients With Early-Stage Breast Cancer : A Secondary Analysis of a Randomized Clinical Trial. In: JAMA Oncology. 2018 ; Vol. 4, No. 12. pp. 1751-1757.
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abstract = "Importance: Whether genetic factors can identify patients at risk for radiation-induced fibrosis remains unconfirmed. Objective: To assess the association between the C-509T variant allele in the promoter region of TGFB1 and breast fibrosis 3 years after radiotherapy. Design, Setting, and Participants: This is an a priori-specified, prospective, cohort study nested in an open-label, randomized clinical trial, which was conducted in community-based and academic cancer centers to compare hypofractionated whole-breast irradiation (WBI) (42.56 Gy in 16 fractions) with conventionally fractionated WBI (50 Gy in 25 fractions) after breast-conserving surgery. In total, 287 women 40 years or older with pathologically confirmed stage 0 to IIA breast cancer treated with breast-conserving surgery were enrolled from February 2011 to February 2014. Patients were observed for a minimum of 3 years. Outcomes were compared using the 1-sided Fisher exact test and multivariable logistic regression. Exposures: A C-to-T single-nucleotide polymorphism at position -509 relative to the first major transcription start site (C-509T) of the TGFB1 gene. Main Outcomes and Measures: The primary outcome was grade 2 or higher breast fibrosis as assessed using the Late Effects Normal Tissue/Subjective, Objective, Medical Management, Analytic scale (range, 0 to 3) three years after radiotherapy. Results: Among 287 women enrolled in the trial, TGFB1 genotype and 3-year radiotherapy-induced toxicity data were available for 174 patients, of whom 89 patients (51{\%}) with a mean (SD) age of 60 (8) years had at least 1 copy of C-509T. Grade 2 or higher breast fibrosis was present in 12 of 87 patients with C-509T (13.8{\%}) compared with 3 of 80 patients without the allele variant (3.8{\%}) (absolute difference, 10.0{\%}; 95{\%} CI, 1.7{\%}-18.4{\%}; P =.02). The results of multivariable analyses indicated that only C-509T (odds ratio, 4.47; 95{\%} CI, 1.25-15.99; P =.02) and postoperative cosmetic outcome (odds ratio, 7.09; 95{\%} CI, 2.41-20.90; P <.001) were significantly associated with breast fibrosis risk. Conclusions and Relevance: To date, this study seems to be the first prospective validation of a genomic marker for radiation fibrosis. The C-509T allele in TGFB1 is a key determinant of breast fibrosis risk. Assessing TGFB1 genotype may facilitate a more personalized approach to locoregional treatment decisions in breast cancer.",
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AU - Grossberg, Aaron

AU - Lei, Xiudong

AU - Xu, Ting

AU - Shaitelman, Simona F.

AU - Hoffman, Karen E.

AU - Bloom, Elizabeth S.

AU - Stauder, Michael C.

AU - Tereffe, Welela

AU - Schlembach, Pamela J.

AU - Woodward, Wendy A.

AU - Buchholz, Thomas A.

AU - Smith, Benjamin D.

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N2 - Importance: Whether genetic factors can identify patients at risk for radiation-induced fibrosis remains unconfirmed. Objective: To assess the association between the C-509T variant allele in the promoter region of TGFB1 and breast fibrosis 3 years after radiotherapy. Design, Setting, and Participants: This is an a priori-specified, prospective, cohort study nested in an open-label, randomized clinical trial, which was conducted in community-based and academic cancer centers to compare hypofractionated whole-breast irradiation (WBI) (42.56 Gy in 16 fractions) with conventionally fractionated WBI (50 Gy in 25 fractions) after breast-conserving surgery. In total, 287 women 40 years or older with pathologically confirmed stage 0 to IIA breast cancer treated with breast-conserving surgery were enrolled from February 2011 to February 2014. Patients were observed for a minimum of 3 years. Outcomes were compared using the 1-sided Fisher exact test and multivariable logistic regression. Exposures: A C-to-T single-nucleotide polymorphism at position -509 relative to the first major transcription start site (C-509T) of the TGFB1 gene. Main Outcomes and Measures: The primary outcome was grade 2 or higher breast fibrosis as assessed using the Late Effects Normal Tissue/Subjective, Objective, Medical Management, Analytic scale (range, 0 to 3) three years after radiotherapy. Results: Among 287 women enrolled in the trial, TGFB1 genotype and 3-year radiotherapy-induced toxicity data were available for 174 patients, of whom 89 patients (51%) with a mean (SD) age of 60 (8) years had at least 1 copy of C-509T. Grade 2 or higher breast fibrosis was present in 12 of 87 patients with C-509T (13.8%) compared with 3 of 80 patients without the allele variant (3.8%) (absolute difference, 10.0%; 95% CI, 1.7%-18.4%; P =.02). The results of multivariable analyses indicated that only C-509T (odds ratio, 4.47; 95% CI, 1.25-15.99; P =.02) and postoperative cosmetic outcome (odds ratio, 7.09; 95% CI, 2.41-20.90; P <.001) were significantly associated with breast fibrosis risk. Conclusions and Relevance: To date, this study seems to be the first prospective validation of a genomic marker for radiation fibrosis. The C-509T allele in TGFB1 is a key determinant of breast fibrosis risk. Assessing TGFB1 genotype may facilitate a more personalized approach to locoregional treatment decisions in breast cancer.

AB - Importance: Whether genetic factors can identify patients at risk for radiation-induced fibrosis remains unconfirmed. Objective: To assess the association between the C-509T variant allele in the promoter region of TGFB1 and breast fibrosis 3 years after radiotherapy. Design, Setting, and Participants: This is an a priori-specified, prospective, cohort study nested in an open-label, randomized clinical trial, which was conducted in community-based and academic cancer centers to compare hypofractionated whole-breast irradiation (WBI) (42.56 Gy in 16 fractions) with conventionally fractionated WBI (50 Gy in 25 fractions) after breast-conserving surgery. In total, 287 women 40 years or older with pathologically confirmed stage 0 to IIA breast cancer treated with breast-conserving surgery were enrolled from February 2011 to February 2014. Patients were observed for a minimum of 3 years. Outcomes were compared using the 1-sided Fisher exact test and multivariable logistic regression. Exposures: A C-to-T single-nucleotide polymorphism at position -509 relative to the first major transcription start site (C-509T) of the TGFB1 gene. Main Outcomes and Measures: The primary outcome was grade 2 or higher breast fibrosis as assessed using the Late Effects Normal Tissue/Subjective, Objective, Medical Management, Analytic scale (range, 0 to 3) three years after radiotherapy. Results: Among 287 women enrolled in the trial, TGFB1 genotype and 3-year radiotherapy-induced toxicity data were available for 174 patients, of whom 89 patients (51%) with a mean (SD) age of 60 (8) years had at least 1 copy of C-509T. Grade 2 or higher breast fibrosis was present in 12 of 87 patients with C-509T (13.8%) compared with 3 of 80 patients without the allele variant (3.8%) (absolute difference, 10.0%; 95% CI, 1.7%-18.4%; P =.02). The results of multivariable analyses indicated that only C-509T (odds ratio, 4.47; 95% CI, 1.25-15.99; P =.02) and postoperative cosmetic outcome (odds ratio, 7.09; 95% CI, 2.41-20.90; P <.001) were significantly associated with breast fibrosis risk. Conclusions and Relevance: To date, this study seems to be the first prospective validation of a genomic marker for radiation fibrosis. The C-509T allele in TGFB1 is a key determinant of breast fibrosis risk. Assessing TGFB1 genotype may facilitate a more personalized approach to locoregional treatment decisions in breast cancer.

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